The present invention relates to new pyrimidine derivatives and the use of the pyrimidine derivatives as medicines. The present invention also relates to new pyridine derivatives and the use of the pyridine derivatives as medicines. The association of the activation of N-type calcium channels is suggested in various diseases, for example, acute stage of ischemic cerebrovascular disorders such as cerebral infarction or intracerebral bleeding (including subarachnoidal hemorrhage); progressive neurodegenerative diseases such as Alzheimer's disease, AIDS related dementia, Parkinson's disease, dementia due to cerebrovascular disorder and ALS; neuropathy caused by head injury; various pains such as pains caused by spinal injury, diabetes or thromboangiitis obliterans, neuropathic pain, migraine, visceral pain and cancer pain; bronchial asthma; various diseases associated with psychogenic stress such as unstable angina and irritable colitis; withdrawal symptoms after addiction to drugs such as emotional disorder and ethanol addiction withdrawal symptoms. The compounds of the present invention can inhibit the N-type calcium channels. The present invention relates to the compounds usable as therapeutic agents for these diseases.
Calcium channels are now classified into subtypes of L, N, P, Q, R and T. Each subtype of calcium channels is organ-specifically distributed. It is known that particularly N-type calcium channels are widely distributed in central nerves, peripheral nerves and adrenomedullary cells and participates in neuronal cell death, regulation of blood catecholamine level and control of senses such as perception.
It has been confirmed that omega-conotoxin GVIA and omega-conotoxin MVIIA, which are peptides selectively inhibiting N-type calcium channels, inhibit the release of excitatory neurotransmitters in the sliced brain preparation. It is also confirmed in animal experiments that they inhibit the progress of neuronal necrosis associated with cerebrovascular disorders. It is generally considered that compounds having a N-type calcium channel blocking activity are clinically effective in the treatment of acute stage of ischemic cerebrovascular disorders such as cerebral infarction or intracerebral bleeding (including subarachnoidal hemorrhage); progressive neurodegenerative diseases such as Alzheimer's disease, AIDS related dementia, Parkinson's disease, dementia due to cerebrovascular disorder and ALS; and neuropathy caused by head injury. Further, it is confirmed in animal tests that omega-conotoxin MVIIA relieves a pain induced by formalin, hot plate and peripheral neuropathy (J. Pharmacol. Exp. Ther. 269 (3) 1117-1123, 1994.; J. Pharmacol. Exp. Ther. 274 (2) 666-672, 1995). Accordingly, omega-conotoxin MVIIA is considered to be clinically effective against various pains such as pain caused by spinal injury, diabetes or thromboangiitis obliterans, neuropathic pain (for example, post herpetic neuralgia, diabetic nephropathy, complex regional pain syndrome, avulsion injury of the brachial plexus, trigeminal neuralgia, pain from spinal injury, central pain and postoperative pain), migraine, visceral pain and cancer pain. In addition, because omega-conotoxin GVIA inhibits the release of catecholamine from cultured sympathetic ganglion cells, exaltation of catecholamine secretion from canine adrenal medulla and the contraction of the isolated blood vessel by electric stimulation of the perivascular nerve, it is considered that compounds having N-type calcium channel-blocking effects are clinically effective against bronchial asthma, various diseases related to psychogenic stress such as unstable angina and irritable colitis (Neuropharmacol., 32, 1141, 1993).
Some peptidergic and non-peptidergic compounds which selectively affect N-type calcium channels have been ever disclosed (see, for example, WO 9313128, WO 9849144, WO9901438 and WO9932446). However, none of them was actually used as a medicine. Some of the compounds which affect N-type calcium channels are also effective against various types of calcium channels of other than N-type (British Journal of Pharmacology, 122 (1) 37-42, 1997). For example, compounds having an antagonistic effect on L-type calcium channels (the channels that are locally distributed in various organs such as vascular smooth muscles) which are very closely related to hypotensive effect, could not be used for diseases for which N-type calcium channel antagonists will be used (such as cerebral stroke, neuralgia, terminal cancer pain and pain of spinal injury). Under these circumstances, the development of a highly active antagonist selective toward N-type calcium channels (the channels that exist in the nervous system) has been eagerly demanded. Recently, improvement in QOL (Quality of life) of the patients is demanded, and medicines to be taken orally are considered to be necessary. Especially, when the medicines are used as analgesic agents to terminal cancer patients and spinal injury victims, less frequent doses and lower dosage will further improve QOL.
However, N-type calcium channel antagonists well-known in the art were yet unsatisfactory for solving this problem because some of them are peptides which cannot be absorbed in the digestive organs or some of them are chemically unstable and, therefore, decomposed in the digestive organs. Though N-type calcium channel antagonists can be absorbed in the digestive organs, the compounds that have less first-pass effect and high durability of drug efficacy cannot be found yet. In addition, some of the well-known compounds are those which have asymmetric carbons. The compounds having an asymmetric carbon have optical isomers, and the activity, toxicity and pharmacokinetics between the isomers are generally believed to be different from each other. Therefore, the chiral compounds having extremely high optical purity or the achiral compounds without asymmetric carbon have been desired in order to develop the pharmaceutical compounds.
Meanwhile, various pyrimidine derivatives and pyridine derivatives have been reported (WO 9204333, WO 9919302, WO 0073279, Laid-open No. 2000-247957, Laid-open No. Hei 7-101940, Laid-open No. Hei 9-241161, Publication No. Sho 48-21949, J. Med. Chem. 31 (6) 1231-1240, 1988. and Chem. Pharm. Bull. 40 (9) 2423-2431, 1992). However, any prior arts did not describe that the reported compounds and similar pyrimidine derivatives and pyridine derivatives inhibited selectively N-type calcium channels. For instance, Laid-open No. Hei 9-241161 describes that 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine derivatives inhibit neuronal necrosis and, therefore, are effective in the treatment of post cerebrovascular disorders. However, the said compound is a voltage-dependent Na+/Ca2+ channel inhibitor (Eur. J. Pharmacol. 336, 283-290, 1997.) and not expected as selective antagonist to N-type calcium channels.